Plant Cell Expressed Recombinant Glucocerebrosidase - Taliglucerase alfa as Therapy for Gaucher Disease in Patients Previously Treated with Imiglucerase

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Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69

Clinical Development of Products to Treat Rare Diseases Ann Pariser, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland USA The Orphan Drug Act (ODA) of 1983 has been highly successful in promoting the development of products intended to treat rare diseases. Since the passage of the ODA, more than 390 Orphan products for the treatment of a wide variety of rare diseases have been approved in the US, approximately 10 of which are for the treatment of lysosomal storage disorders (LSD). However, despite these successes, considerable unmet medical needs for the patients with LSD remain. Designing clinical trials for investigational agents for LSD is challenging. LSD are amongst the rarest of Orphan disorders with few patients available for study, which usually necessitates multi-center trials and international collaboration. Additionally, LSD are a highly heterogeneous collection of diseases with diverse clinical presentations and progression, and substantial phenotypic variability within disorders. This diversity requires individualized approaches to overall clinical development, trial designs, and selection of outcome measures and patient populations for study. Some examples of successful clinical development of products to treat LSD will be presented, which illustrate the scientific rationale behind the individual programs, the level of evidence to define clinical benefit, and study design characteristics unique to the disease and drug under study. doi:10.1016/j.ymgme.2011.11.125

Plant Cell Expressed Recombinant Glucocerebrosidase - Taliglucerase alfa as Therapy for Gaucher Disease in Patients Previously Treated with Imiglucerase Gregory Pastores a, Paul Fernhoff b, Jeffrey Szer c, Milan Petakov d, Timothy Cox e, Pilar Giraldo f, Hanna Rosenbaum g, Dominick Amato h, Eugen Mengel i, Raul Chertkoff j, Einat Almon-Brill j, Ari Zimran k, a New York University School of Medicine, New York, NY, USA, b Department of Human Genetics, Emory University School of Medicine, Decatur, GA, USA, cClinical Haematology and Bone Transplant Service, Royal Melbourne Hospital, 3050 Victoria, Australia, dClinical Center of Serbia, Institute of Endocrinology, Diabetes and Metabolic Diseases, Dr Subotica 13, 11000 Belgrade, Serbia, eDepartment of Medicine, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK, fHospital Universitario Miguel Servet, Servicio de Haematologia Planta baja, P Isabel, La Catolica 1–3, 50009, Zaragoza, Spain, gHaematology Ambulatory Services, Rambam Medical Center, 8 Haaliya St., Haifa 31096, Israel, hMount Sinai Hospital, 600 University Avenue, Room 438, Toronto, Ontario, M5G 1X5, iVilla Metabolic ZKJM MC Gutenberg-University Mainz, Langenbeckstr. 1 Geb. 907, 1.OG MAINZ, 55131 DEU, Germany, jProtalix Biotherapeutics, Carmiel, Israel, kGaucher Clinic, Shaare Zedek Medical Center, 12 Bayt St., Jerusalem 91031, Israel Taliglucerase alfa is a carrot-cell-expressed beta-glucocerebrosidase formulation developed as a treatment for Gaucher disease (GD). This report describes a nine month Phase 3 worldwide multicenter, open-label, switch-over trial with taliglucerase alfa in patients with GD previously treated with imiglucerase. Study objective: assessment of the safety and efficacy of taliglucerase alfa in GD patients, 2 years or older, who have been receiving imiglucerase enzyme replacement therapy for at least 2 years and on a stable maintenance regimen. Patients were evaluated for disease stability and enrolled in a 12week evaluation period to establish stability of their hematological parameters. For patients whose imiglucerase regimen was changed

due to drug shortage, eligibility was based on historical data of disease stability. Eligible patients were switched from imiglucerase to a comparable dose of taliglucerase and received a total of 20 infusions, given every two weeks with a dose equal to the patient's previous imiglucerase dose. Safety endpoints were adverse events, clinical laboratory tests, electrocardiogram, echocardiography, pulmonary function test and antibody formation. Efficacy endpoints were spleen and liver volumes, platelets, and hemoglobin levels. The control for this study was each patient's previous historical clinical and stability laboratory measurements while treated with imiglucerase. Patients enrolled in the trial were treated with taliglucerase alfa , with doses ranging from 10–60 U/kg every other week and treated for 9 months. The analyzed data (to be presented) supports the efficacy and safety of taliglucerase alfa in patients switched from imiglucerase. One patient experienced a hypersensitivity reaction. The efficacy data demonstrate that mean hemoglobin and platelet count, spleen volume and liver volume remained stable. doi:10.1016/j.ymgme.2011.11.126

Immunological Challenges in Late-Onset Pompe Disease Treated with Enzyme Replacement Therapy Trusha Patel, Suhrad Banugaria, Stephanie DeArmey, Joanne Mackey, Priya Kishnani, Duke University, Durham, North Carolina, USA Late-onset Pompe disease (LOPD) is clinically heterogeneous and involves skeletal and respiratory muscles. Since the advent of enzyme replacement therapy (ERT) with alglucosidase alfa, the immune response to ERT is being better understood. We have previously reported poor clinical outcome in the approximately 36% of infantile patients who develop high, sustained antibody titers (HSAT). Clinical studies demonstrated that 1% of patients develop anaphylaxis or cardiac arrest and 14% develop allergic reactions affecting at least 2–3 body systems while on ERT. Data in late-onset patients is currently limited to Late-Onset Treatment Study (LOTS), in which approximately 15% developed HSAT. Here, we present a systematic evaluation of antibody titers and infusion- associated reactions (IARs) in 22 LOPD patients (age range 13–71, mean 51.2, median 56) on ERT. IgG antibodies and IARs were monitored over time. Nine patients experienced significant IARs (7 hypersensitivity reactions, 2 milder reactions involving 2–3 body systems). Two patients discontinued ERT due to lack of physician support to desensitize and the remaining seven were successfully desensitized using an individualized desensitization approach reported by our group (El-Gharbawy et al, 2011). Three patients who developed IARs and one additional patient (4/22 total) developed HSAT ranging from 51,200 to 409,600 at >6 months on ERT. Given the availability of desensitization protocols and immunomodulatory strategies to enhance the safety and efficacy of ERT, this study emphasizes the importance of close monitoring of immunogenicity in LOPD and the need for better monitoring tools to better understand the role of HSAT in late-onset Pompe disease. doi:10.1016/j.ymgme.2011.11.127

Longitudinal Study of Cognition in Patients with Niemann-Pick Disease, Type C Marc Patterson a, Forbes Porter b, Tanya Brown a, Rebecca Vaurio c, a Mayo Clinic, Rochester, MN, USA, bNational Institutes of Health, Bethesda, MD, USA, cKennedy Krieger Institute, Baltimore, MD, USA